Method of inhibiting inflammation using 1,4-disubstituted-methylenedioxy-2(1h)-quinazolinones and quinazolinthiones

ABSTRACT

Disclosed are compounds of the class of 1-alkyl-4-phenyl and 4(2-thienyl)-6,7-methylenedioxy-2(1H)-quinazolinones and quinazolinthiones, including the 3,4-dihydro derivatives thereof, useful as pharmaceutical agents, e.g., as anti-inflammatory agents. Such compounds, e.g., 1-isopropyl-4-phenyl-6,7methylenedioxy-2(1H)-quinazolinones and -isopropyl-4-phenyl-6,7methylenedioxy-2(1H)-quinazolinthiones, may be prepared by reacting the corresponding N-alkyl-N(3,4methylenedioxyphenyl)urea or thiourea with an aromatic aldehyde, e.g., benzaldehyde, in the presence of an acid at elevated temperatures to obtain the 3,4-dihydro-2(1H)-quinazolinones or 3,4-dihydro-2(1H)-quinazolinthiones which may then be oxidized to the corresponding 3,4-unsaturated compounds.

United States Patent [191 Cooke et al.

[ Dec. 24, 1974 METHOD OF INHIBITING INFLAMMATION USING1,4-DISUBSTITUTED-METHYLENEDIOXY- 2( lH)-QUINAZOLINONES ANDQUINAZOLINTHIONES [75] Inventors: George A. Cooke, Denville; William J.Houlihan, Mountain Lakes, both of NJ.

[73] Assignee: Sandoz-Wander, Inc., Hanover, NJ.

[22] Filed: Apr. 13, 1973 [21] Appl. No.: 351,093

Related US. Application Data [60] Division of Ser. No. 141,010, May 6,1971, Pat. No. 3,748,331, which is a continuation-impart of Ser. No.34,902, May 5, 1970, abandoned, which is a continuation-in-part of Ser.No. 881,325, Dec. 1, 1969, abandoned.

[52] US. Cl. 424/251 [51] Int. Cl A61k 27/00 [58] Field of Search424/251 [56] References Cited UNITED STATES PATENTS 3,305,553 2/1967Hoefle et al. 260/256.4

Primary Examiner-James A. Patten Attorney, Agent, or Firm-Gerald D.Sharkin; Richard E. Vila [57] ABSTRACT Disclosed are compounds of theclass of l-alkyl-4- phenyl and 4-(2-thienyl)-6,7-methylenedioxy-2(11-1)-quinazolinones and quinazolinthiones, including the 3,4-dihydroderivatives thereof, useful as pharmaceutical agents, e.g., asanti-inflammatory agents. Such compounds, e.g.,1-isopropyl-4-phenyl-6,7-methy1enedioxy-2(1l-l)-quinazolinones and-isopropy1-4-phenyl- 6,7-methylenedioxy-2( lH)-quinazolinthiones, may beprepared by reacting the corresponding N-alkyl-N(3,4-methylenedioxyphenyl)urea or thiourea with an aromatic aldehyde,e.g., benzaldehyde, in the presence of an acid at elevated temperaturesto obtain the 3,4- dihydro-2(1H)-quinazolinones or 3,4-dihydro-2(1H)-quinazolinthiones which may then be oxidized to the corresponding3,4-unsaturated compounds.

2 Claims, No Drawings METHOD OF INHIBITING INFLAMMATION USING 1,4-rsygs11TUTED-METHYL NEDIoXY-mum- QUINAZOLINONES AND QUINAZOLINTHIONESThis application is a division of copending application Ser. No. 141,010filed May 6, 1971, now U.S. Pat. No. 3,748,331, which is acontinuation-in-part of application Ser. No. 34,902, filed May 5, 1970,now abandoned, which in turn is a continuation-in-part of applicationSer. No. 881,325, filed Dec. 1, 1969 and also abandoned.

This invention relates to cyclic compounds, and more particularly to1-substituted-4-cyclosubstitutedmethylenedioxy-2(ll-l)-quinazolinonesand quinazolinthiones having the methylenedioxy fraction joined atadjacent positions in the benzene portion of the quinazolinyl moiety,and to preparation of such compounds. The invention also relates topharmaceutical compositions and methods employing said compounds.

The compounds of the invention may be represented by the formula I:

in which Z is oxygen or sulfur,

R signifies an alkyl radical of one to five carbon atoms,

e.g., methyl, ethyl, isopropyl and t-butyl; cyclo (lower)alkyl of threeto six carbon atoms; e.g., cyclopropyl and cyclohexyl; orcyclo(lower)alkyl(- lower) straight chain alkyl of four to seven totalcarbon atoms in which the cycloalkyl is of three to six carbon atoms andthe straight chain alkyl is of one to three carbon atoms, e.g.,cyclopropylmethyl,

R' is Y is hydrogen; halo of atomic weight of from 19 to 36, e.g.,fluoro; lower alkyl of one to three carbon atoms, e.g., methyl; loweralkoxy of one to three carbon atoms, e.g., methoxy; nitro; ortrifluoromethyl;

Y is hydrogen; halo of atomic weight of from 19 to 36; lower alkyl ofone to three carbon atoms; or lower alkoxy of one to three carbon atoms;or

Y and Y together form methylenedioxy; and

R is hydrogen; halo of atomic weight of from 19 to 36, e.g., chloro; orlower alkyl of one to three carbon atoms, e.g., methyl.

The compounds of formula 1 may be prepared by subjecting a correspondingcompound of formula II:

R O l C 13 .R II

in which R and R are as defined, to oxidation in an organic solvent.

The preparation of compounds I from compounds 11 by oxidation may beconveniently carried out in an inert organic solvent at temperatures inthe range of 0C. to 120C., typically 15C. to C., where Z is oxygen and20C. to 60C. where Z is sulfur. The oxidiziagents which may be employedare of known type suitable for converting an organic amino moiety to animino moiety. Representative of such oxidizing agents are the alkalimetal permanganates, such as sodium or potassium permanganate, manganesedioxide and mercuric acetate. The permanganates are the preferredoxidizing agents for producing the quinazolinones, while manganesedioxide, maintained essentially free of water, is the preferredoxidizing agent for making the quinazolinthiones. The organic solventmay be any of several conventional organic solvents including by way ofillustration methylene chloride, the lower alkanols, e.g., methanol andethanol, the aromatic solvents, e.g., benzene and the ethers includingthe cyclic ethers, e.g., dioxane. The product of formula 1 may beisolated from the reaction by working up by established procedures.

The compounds of formula ll may be prepared by reacting anN-alkyl-N-(3,4 methylenedioxyphenyl)urea or thiourea of formula 111:

0 III with a compound of the formula IV:

R'Cl-lO wherein Z, R and R are as defined, at elevated temperatureswhereby compounds of the formula 11 are obtained.

The reaction of compound 111 with compound 1V is carried out at elevatedtemperatures in the range of 30C. to C., preferably 50C. to 100C. Thereaction is suitably carried out in the presence of an acid as catalystand dehydrating agent which is otherwise nonreactive with compounds llland IV, for example, an inorganic mineral acid, such as hydrochloricacid (hydrogen chloride in an aromatic solvent) or an organic acid suchas trifluoroacetic acid, oxalic acid or an arylsulfonic acid or analkylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acidand methanesulfonic acid, preferably the latter. The amount of acidcatalyst is desirably control a minor amount not substantially exceedingabout one molar equivalent based on the compound Ill, and is mostpreferably a minor.

catalytic amount between 0.005 to 0.5 molar equivalent based on theurea. The conducting of the reaction under anhydrous or nearly anhydrousconditions is important to obtaining effective results. The reaction isconveniently carried out in an organic solvent which may be any ofseveral conventional organic solvents providing an inert reactionmedium, preferably an aromatic solvent such as benzene toluene and thelike. Depending upon known factors such as reaction temperature, etc.the reaction may take typically between 1 to 50 hours. The reactionproduct of formula 11 may be isolated from the reaction mixture byworking up by established procedures.

We had postulated that the preparation of compounds II by reaction ofcompounds Ill and IV proceeds through an intermediate of the formula A:

l N \C=Z CH2 i f dI-I I A wherein Z, R and R are as defined. In ourexperimentation conducted with reference to the more preferredembodiments of the invention it was evident that an intermediate offormula A had been formed on merely a transient basis, and that thereaction may directly produce compounds II in good yields in essentiallya single stage operation when conducted under the preferred conditionsas demonstrated, for example, in Step B of Example 1, hereinafter.

The urea compounds of formula III, i.e., those in which Z is oxygen, arepreferably prepared by subjecting a compound of the formula V:

\ -I IH wherein R is as defined, to reaction with isocyanic acid whichis provided in a conventional manner by forming in-situ from an alkalimetal isocyanate (also obtainable and known as alkali metal cyanates)and a suitable acid such as a lower aliphatic carboxylic acid,preferably acetic acid. The reaction may be suitably carried out attemperatures in the range of C. to 50C. and in an organic solvent mediumwhich may be conventionally a lower aliphatic carboxylic acid such asexcess acetic acid.

The urea compounds of formula Ill may also be provided starting with acompound of formula V by subjecting the latter to reaction withnitrourea at temperatures typically in the range of 80C. to 120C. in aninert organic solvent of conventional type, preferably a lower alkanolsuch as ethanol.

The compounds of formula Ill in which Z is sulfur may be suitablyprepared by subjecting a compound of the formula VI:

wherein R is as defined and A is the residue of an acid halide, toalkaline hydrolysis at elevated temperatures in the range of 50C. to140C., preferably 80C. to lC.

The hydrolysis is suitably effected employing an alkali metal hydroxide,preferably sodium or potassium hydroxide. The reaction is carried out ina suitable liquid solvent medium preferably comprising water and a watermiscible inert organic solvent of conventional type such as an ether,including the cyclic ethers, preferably dioxane.

The reaction product of formula III may be isolated from theaforementioned reactions by working up by conventional procedures.

The compounds of formula V may be suitably prepared from known materialsby established procedures. A preferred method of preparation ofcompounds V employs as starting material a compound of formula VII:

and involves subjecting said compound V" to known type protectionreactions such as to reaction with a trialkylorthoformate followed bytreatment with a strong acid such as sulfuric acid or to tosylation,alkylation and detosylation, all in a manner known per se. It will benoted that compounds V in which R is a cycloalkyl or branched alkyl withthe branching occurring on the carbon atom attached to amino nitrogen,e.g., R is isopropyl, may be most conveniently and preferably preparedby reacting directly compound Vll with the appropriate alkyl halide, asillustrated hereinafter in Step A of Example 1, in the presence of anacid binding agent.

The compounds of the formula VI may be prepared by subjecting a compoundof the formula V, above, to reaction with an isothiocyanate of formulaVlll:

wherein M is a cation, and an acid halide of the formula IX:

wherein A' is as previously indicated and X is halogen, preferablychloro, or to the action of the reaction product of said acid halide andisothiocyanate.

The preparation of compounds Vl from a compound V is convenientlycarried out in an inert solvent medium at temperatures in the range of10C. to 80C., preferably 30C. to C. The reaction may be understood asincluding the reaction of compound V with the reaction product of theacid halide of formula IX and isothiocyanate of formula Vlll. For thisreason, it is generally preferred to first react the acid halide offormula IX and compound VIII and then add the starting compound V to theresulting reaction mixture. The reaction of the acid halide andisothiocyanate is preferably initiated at lower temperatures in therange of 10C. to 40C. As acid halides one employs any of theconventional acid halides which do not carry substituents or functionalgroups leading to undesired reactions. The more suitable materials arerepresented, for example, by acetyl chloride and benzoyl chloride,preferably benzoyl chloride. The preferred compounds Vlll are those mostreadily reacting with the acid halide to eliminate as by-product ahalide of the cation M. The preferred cations M may be represented, forexample, by a cation of an alkali metal, e.g., sodium, and by the cationof ammonia, i.e., the ammonium salt. The more preferred compound VIII isammonium isothiocyanate. Organic solvents suitable for the reaction areof con- VII ventional type which provide an inert medium. Such solventsinclude by way of example, benzene, the lower alcohols, ketones andcyclic ethers, preferably acetone. The reaction product of formula VImay be recovered from the reaction by working up by conventionalprocedures. It will also be noted that in going from compound V tocompound III complete isolated and/or recovery of the intermediatecompound VI is not necessary, and that in certain cases the reactionmixtures from the reaction of compounds V and VIII may contain varyingamounts of the compound of formula III in which Z is sulfur.

The compound of formula VII can be prepared from known materials byestablished procedures, for example, by subjecting methylenedioxybenzeneto nitration to obtain a 3,4-methylenedioxynitrobenzene which is thensubjected to catalytic reduction with hydrogen employing a platinumoxide or palladium on charcoal as catalyst to obtain said compound offormula VII.

The compounds of formula I and also the intermediates of the formula IIare useful because they possess pharmaceutical activity in animals. Inparticular, the compounds I and II are useful as anti-inflammatoryagents as indicated by the Carrageenan-induced edema test in rats. Forsuch use, the compounds may be combined with a pharmaceuticallyacceptable carrier, and such other conventional adjuvants as may bedesired, and preferably administered orally in such forms as tablets,capsules, elixirs, suspensions and the like. For the above-mentioneduse, the dosage administered will, of course, vary depending upon knownfactors such as the particular compound used and mode of administration.However, in general, the compounds of formula I in which Z is oxygenprovide satisfactory results when administered at a daily dose of fromabout 0.15 milligrams to 180 milligrams per kilogram of body weight,preferably given in divided doses 2 to 4 times a day, with daily dosagefor large mammals ranging from between about milligrams to 1,000milligrams and individual doses between 3 milligrams to 500 milligrams.For the compounds of the formula I in which Z is sulfur satisfactoryresults are obtained at a daily dose of from 0.2 to 180 milligrams perkilogram of body weight with daily dosage for large mammals beingbetween 16 to 1,500 milligrams and divided doses between 4 and750milligrams. The compounds of formula II in which Z is oxygen ingeneral provide satisfactory results when administered at a daily doseof from about 2 milligrams to 200 milligrams per kilogram of bodyweight, preferably given in divided doses, with daily dose for largemammals ranging between 140 milligrams to 2,000 milligrams andindividual doses ranging between 35 to 1,000 milligrams. For thecompounds of the formula II in which Z is sulfur satisfactory resultsare obtained at a daily dose of from 3 to 250 milligrams per kilogram ofbody weight with daily dosage for large mammals being between 200 to2,500 milligrams and divided doses between 50 and 1,250 milligrams.

The compounds of the formulae I and II are also useful as analgesics asindicated by application of pressure to yeast-inflammed foot of the rat(oral administration). They are also useful as anti-pyretics asindicated by inhibition of yeast-induced fever in rats (oraladministration). For such uses, the compound may be administered toobtain satisfactory results in modes and forms similar to those employedin the treatment of inflammation and at dosages indicated above asapplicable for the use of the compound in the treatment of inflammation.

The intermediates of the formula III are also useful because theyexhibit pharmacological activity in animals. In particular, thecompounds of the formula III are useful as anti-inflammatory agents asindicated by the Carrageenan-induced edema test in rats. Such compounds,which may be administered in modes and forms similar to the compounds offormula I, generally provide satisfactory anti-inflammatory results whenadministered at a daily dose of from 2 to 200 milligrams per kilogram ofanimal body weight with daily dosage for large mammals beingin the rangebetween about 140 to 2,000 milligrams and divided doses between 35 and1,000 milligrams.

For the above usage, oral administration with carriers may take place insuch conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g., inert diluents such as calcium carbonate, sodium carbonate,lactose and talc, granulating and disintegrating agents, e.g., starchand alginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearic acid and talc. Thetablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcompositions, e. g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylene sorbitan' monooleate) and preservatives(ethyl-phydroxybenzoate). Capsules preferably contain the activeingredient admixed with an inert solid diluent, e.g., calcium carbonate,calcium phosphate and kaolin. The preferred pharmaceutical compositionsfrom the standpoint of preparation and ease of administration are solidcompositions, particularly solid diluent-filled capsules and tablets.

A representative individual dose form suitable for oral administrationfour times a day is a capsule prepared by conventional techniques andcontaining the following ingredients:

Ingredient Parts by Weight methylenedioxy-2( IH)- quinazolinone Inertsolid diluents: e.g., kaolin 200 Preferred pharmaceutical compounds ofthe invention are those of formula I in which Z is oxygen and those inwhich R is isopropyl, more especially 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)- quinazolinone,1-isopropyl-4(p-fluorophenyl)-6 ,7-methylenedioxy-2(ll-I)-quinazolinone, 1-isopropyl-4- 7(m-fluorophenyl)-6,7-methylenedioxy-2(1H)- quinazolinone andl-isopropyl-4-phenyl-6,7- methylenedioxy-2( 1H )-quinazolinthione.

The following examples are for purposes of illustration only.

EXAMPLE A N-isopropyl-3 ,4-methylenedioxyaniline STEP A: Preparation ofl-nitro-3,4-

- methylenedioxybenzene.

To l50mls. of concentrated nitric acid cooled to and maintained at 0C.is added 100 gms. of methylenedioxybenzene dropwise with vigorousstirring. At the end of the addition, the reaction mixture is dilutedwith several volumes of water, the precipitated solids collected byvacuum filtration and washed with several portions of water.Recrystallization of the crude solids from methanol provided 1-nitro-3,4- methylenedioxybenzene, m.p. l38l4lC.

STEP B: Preparation of l-amino-3 ,4- methylenedioxybenzene To a solutionof 38 gms. of l-nitro-3,4- methylenedioxybenzene in 75 mls. of absoluteethanol is added 1.5 gms. of percent palladium on carbon. The resultingmixture is hydrogenated at approximately 4 atmospheres pressure ofhydrogen and ambient temperature for 4 hours. The catalyst is removed byfiltration and the filtrate concentrated to a syrup. Trituration of thesyrup with petroleum ether (b.p. 3060C.) causes solidification andrecrystallization from the same solvent provides l-amino-3 ,4-methylenedioxybenzene, m.p. 37C. STEP C: Preparation of N-isopropyl-3,4-methylenedioxyaniline To a solution of 197 gms. of l-amino-3,4-

EXAMPLE 1 l-Isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)- quinazolinone.

CH3 CH3 STEP A: Preparation of methylenedioxyphenyl)urea To a solutionof 14.7 gm. of N-isopropyl-3,4- methylenedioxyaniline, prepared as inExample A, in 200 ml. of glacial acetic acid, cooled to 10-l8C., isadded 4.9 gm. of sodium isocyanate (sodium cyanate) in several portions.The resulting mixture is then stirred at ambient temperature for 15hours. At the end of this time, the solvent is stripped at reducedpressure and the solid residue treated with 300 ml. of 2N sodiumhydroxide. The resulting mixture is extracted with chloroform, dried andevaporated. The gum thus obtained is recrystallized from cyclohexane toobtain N-isopropyl- N-(3,4-methylenedioxyphenyl)urea, m.p. 1 l6l 19C.STEP B: Preparation of l-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2( lH)-quinazolinone.

A solution of 10.3 gm. of N-isopropyl-(3,4- methylenedioxyphenyl)urea,7.1 ml. of benzaldehyde, and 3 drops of methanesulphonic acid in 250 ml.of toluene is refluxed under a water separator for 21 hours. The cooledsolution is then washed with 200 ml. of water, dried and evaporated toyield a powder. This product is decolorized in hot propanol with a smallamount of activated charcoal and recrystallized from propanol to obtainl-isopropyl-4-phenyl-6,7methylenedioxy- 3,4dihydro-2( lH)-quinazolinone,m.p. l69l 72C. STEP C: Preparation of l-isopropyl-4-phenyl-6,7-methylenedioxy-2( 1H )-quinazolinone To a solution of 8.5 gm. ofl-isopropyl-4-phenyl-6,7- methylenedioxy-3,4-dihydro-2( 1H)-quinazolinone in 225 ml. of p-dioxane, cooled to l0-l3C., is addeddropwise a solution of 4.3 gm. of potassium permanganate in 185 ml. ofwater. When the addition is complete, 2 ml. of formalin solution areadded. Precipitated solids are removed by filtration and the solventsstripped from the filtrate at reduced pressure. The residue isdecolorized with activated charcoal in ethyl acetate and recrystallizedfrom ethyl acetate to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)- quinazolinone, m.p.l87l9lC.

N-isopropyl-N-(3,4-

EXAMPLE 2 l-lsopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinthione.

cm CH:

N CH2 I STEP A: Preparation of N-lsopropyl-N-(3,4-

methylenedioxyphenyl)-N-benzoyl thiourea.

To a solution of l6.3 grams benzoyl isothiocyanate, prepared byrefluxing 13.6 grams of dried sodium isothiocyanate with 17 grams ofbenzoyl chloride in 30 ml. of benzene, is slowly added, at roomtemperature, 28 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)- amine(prepared as in Example A) in ml. benzene. The reaction mixture isstirred for 30 minutes at 20C.

and a solid forms which is recrystallized from benzene to yieldN-isopropyl-N-(3,4-methylenedioxyphenyl)- N-benzoyl thiourea melting at152-154C.

STEP B: Preparation of N-lsopropyl-N-(3,4-methylenedioxyphenyl)-thiourea.

To a stirred solution consisting of 45 ml. of dioxane and 200 ml. ofwater is added 27 grams of sodium hydroxide and the whole stirred untilcomplete solution takes place. To this solution is added 17 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)-N-benzoyl thiourea. The resultingmixture is heated to reflux for 48 hours and then cooled to C. Theresulting white solid is crystallized from benzene to obtain N-isopropyl-N-(3,4-methylenedioxyphenyl)-thiourea melting at l49l5lC.

STEP C: Preparation of 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione.

A solution of 30 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)thiourea, 27.6 mls. of benzaldehyde, and 2 mls. ofmethanesulphonic acid in 500 ml. of toluene is refluxed under a DeanStark water separator for 4 hours, during which 2 ml. water iscollected. The filtered solution is then evaporated to yield a powder.This product is recrystallized from dioxane and water to obtainl-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinthione, m.p. 2l5218C.

STEP D: Preparation of 1-isopropyl-4-phenyl-6,7- methylenedioxy-2(lH)-quinazolinone.

A mixture of 2 grams of l-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2( l H )-quinazolinthione, 100 ml. ofmethylene chloride and 4 grams of manganese dioxide is stirred for 48hours at room temperature. Precipitated solids are removed by filtrationand the filtrate evaporated to dryness. The residue is recrystallizedfrom ethyl acetate and then methanol and then eluted with benzene in asilica gel column to give I- isopropyl-4-phenyl-6,7-methylenedioxy2(1H)-quinazolinthione, m.p. 202205C.

EXAMPLE 3 Following substantially the procedure of Example 1 thefollowing compounds of the invention are prepared:

A-l. l-isopropyl-4-(m-fluorophenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l65-167C.

A-2. l-isopropyl-4-(m-fluorophenyl)-6,7-

methylenedioxy-2-( lH)-quinazolinone, m.p. 169-l70C.

B-l. l-isopropyl-4-(m-methoxyphenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l67-168C.

B-2. l-isopropyl-4-(m-methoxyphenyl)-6,7-

methylenedioxy-2( 1H )-quinazolinone, m.p. l89l91C.

C-l. l-isopropyl-4-( p-methylphenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. 192-194C.

C-2.l-isopropyl-4-(p-methylphenyl)-6,7-methylenedioxy-2(1H)-quinazolinone,m.p. l88l90C.

D-l. l-isopropyl-4-(o-nitrophenyl)-6,7-

methylenedioxy-3 ,4-dihydro-2( l H quinazolinone, m.p. 202205C.

D-2.l-isopropyl-4-(o-nitrophenyl)-6,7-methylenedioxy-2(lH)-quinazolin0ne,m.p. l48l50C.

El. l-isopropyl-4( 5 -chloro-2-thienyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l62-164C.

E-2. l-isopropyl-4-(5-chloro-2-thienyl)-6,7-

methylenedioxy-2( l H )-quinazolinone, m.p. 192-201C.

F-l. l-isopropyl-4-('3,4-methylenedioxyphenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l45l47C.

F-2. l-isopropyl-4-(3,4-methylenedioxyphenyl)-6,7-

methylenedioxy-2( 1H )-quinazolinone, m.p. 234235C. G-l.l-isopropyl-4-(m-nitrophenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. 218220;

G-2. l-isopropyl-4-(m-nitrophenyl)-6,7-methylenedioxy-2(lH)-quinazolinone, m.p. 230-232;

H-l. 1-isopropyl-4-(o-methylphenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l72-l74;

H-2.1-isopropyl-4-(o-methylphenyl)-6,7-methylenedi0xy-2(1H)-quinazolinone,m.p. l55-l57;

l-l. 1-isopropyl-4-(p-fluorophenyl)-6,7-

methylenedioxy-3,4-dihydro-2( 1H quinazolinone, m.p. l63-l66;

[-2.l-isopropyl-4-(p-fluorophenyl)-6,7-methylenedioxy-2(1H)-quinazolinone,m.p. 238-240;

J-l. i-isopropyl-4-(3,4-dichlorophenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone, m.p. l55157;

J-2. l-isopropyl-4(3,4-dichlorophenyl)-6,7-

methylenedioxy-2( l H )-quinaz0linone, m.p. 239-242;

K-l. l-methyl-4-phenyl-6,7-methylenedioxy-3 ,4- dihydro-2(lH)-quinazolinone, m.p. 23l-232;

K-2. l-methyl-4-phenyl-6,7-methylenedioxy-2(1H)- quinazolinone, m.p.257260;

L-l. 1-cyclopropylmethyl-4-phenyl-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinone.

L-2. l-cyclopropylmethyl-4-phenyl-6,7-methylenedioxy-2( 1H)-quinazolinone.

EXAMPLE 4 Following substantially the procedure of Example 2 thefollowing compounds of the invention are prepared:

A-l. 1-isopropyl-4-(m-fluorophenyl )-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinthione, m.p. 200-203C.

A-2. l-isopropyl-4-(m-fluorophenyl)-6,7-methylenedioxy-2(lH)-quinazolinthione, m.p. 2l02l4C. B-l.l-isopropyl-4(p-isopropylphenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinthione, m.p. ]55-l 57C.

B-2. l-is0propyl-4-(p-isopropylphenyl)-6,7-

methylenedioxy-2(1H)-quinazolinthione, m.p. l67-l70C.

C-l. 1-isopropyl-4-(p-fluorophenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinthione, m.p. 198-l99C.

C-2. l-isopropyll4-(p-fluorophenyl)-6,7methylenedioxy-2(lH)-quinazolinthione, m.p. 220-223C. D-l. l-isopropyl-4(m-nitrophenyl)-6,7-

methylenedioxy-3,4-dihydro-2(1H)- quinazolinthione, m.p. l l5l 17C D-2.1-isopropyl-4-(m-nitrophenyl)-6,7-methylene- Y is hydrogen, halo ofatomic weight of from l9 to dixy-2(lH)-quinazolinthione, m.p. l99202C.36, lower alkyl, lower alkoxy, nitro or trifluoro- What is claimed is:th l;

1. The method Of inflammation in animals Y is hydrogen, halo of atomicweight of from [0 comprising administeringapharmacologically effective 3lower alkyl, lower aikoxy, nitro or t ifl amount of a compound of theformula methyl;

Y is hydrogen, halo of atomic weight of from 19 to r 36, lower alkyl orlower alkoxy; or Y and Y" together from methylenedioxy; and

R is hydrogen, halo of atomic weight of from 19 to o 36 or lower alkyl.

2. The method of inhibiting inflammation in animals comprisingadministering a pharmacologically effective amount of a compound of theformula wherein Z is oxygen or sulfur R is lower alkyl,cyclo(lower)alkyl, or cyclo(lower) alkyl(lower)straight chain alkyl IllR is o C:r

wherein Z, R and R are as defined in claim l.

1. THE METHOD OF INHIBITING INFLAMMATION IN ANIMALS COMPRISINGADMINISTERING A PHARMACOLOGICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THEFORMULA
 2. The method of inhibiting inflammation in animals comprisingadministering a pharmacologically effective amount of a compound of theformula